Alvise Polese

Nifedipine, a new antihypertensive with rapid action.

Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered sublingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176189 and to 47/19 mm Hg by an additional 10 mg.

Upward shift of the lower range of coronary flow autoregulation in hypertensive patients with hypertrophy of the left ventricle.

BackgroundAt any given perfusion pressure, coronary reserve is expressed by the difference between autoregulated and maximally vasodilated flow. In hypertension the raised coronary resistance reduces the steepness of the pressure-flow relationship at maximal vasodilatation. In the presence of cardiac hypertrophy the line of autoregulated flow becomes higher. For these reasons coronary reserve is reduced and the point at which baseline flow approaches the maximal achievable flow might be shifted to a higher perfusion pressure. Thus, any reduction below this elevated and critical value of pressure would lower the coronary flow. Methods and ResultsThe investigated patients were normotensive (controls, nine) and hypertensive with normal (group I, seven) or augmented LV mass index because of concentric LV hypertrophy (group II, eight). All had effort-induced angina and angiographically normal left epicardial branches. Flow in the great cardiac vein was measured by thermodilution in the baseline and during stepwise (5 mm Hg every 5 minutes) decrease of the coronary perfusion pressure with a titrated nitroprusside i.v. infusion; perfusion pressures of 60 mm Hg in the controls and 70 mm Hg in the hypertensives were taken as end points. Baseline flow averaged 102 ml/min in normotensives, 104 ml/min in hypertensive group I and 148 ml/min in hypertensive group II. At the end points flow was similar to baseline in the controls and group I. In group II coronary flow started to decline and myocardial 02 extraction started to slightly but significantly rise at perfusion pressures of 90-80 mm Hg; at the end point flow was reduced by 26% (p<0.01 from baseline). The perfusion patterns did not seem to be related to the changes in tension-time index and heart rate. ConclusionsThe association of high blood pressure (reduced ability of the coronary arterioles to dilate) and hypertrophy of the myocardium (augmented baseline coronary flow) may shift the point of exhaustion of coronary reserve to a higher perfusion pressure and make the myocardium vulnerable to treatment-induced relative hypertension. (Circulation 1991;83:845–853)

Clinical use of a calcium antagonistic agent (nifedipine) in acute pulmonary edema

Nifedipine induces vascular smooth muscle relaxation through a calcium antagonistic action. The possibility of clinical use of the drug as a ventricular unloading agent has been explored in this study. In patients with hypertensive (seven cases), primary (seven cases) or rheumatic (aortic insufficiency five cases, mitral regurgitation five cases) cardiac disease, nifedipine, administered in a single sublingual dose (10 mg), relieved acute pulmonary edema. Circulatory variations from control were the following: decrease of systemic and pulmonary arterial pressures, and of vascular resistances, of pulmonary wedge pressure, of left ventricular diastolic and systolic dimensions (echocardiography); increase of cardiac and stroke index, of left ventricular mean rate of circumferential fiber shortening, of left and right mean pre-ejection delta P/delta t and mean rate of ejection; improvement of forward output in primary and rheumatic disease. Nifedipine benefits acute congestive heart failure by sustained fall of both preload and afterload and, possibly, by an enhanced contractility. It seems to have an appropriate indication in cases in which left ventricular afterload reduction is desirable.

Short- and long-term efficacy of a calcium-antagonistic agent (nifedipine) combined with methyldopa in the treatment of severe hypertension.

Nifedipine induces a potent vasodilating and antihypertensive effect in man through a calciumantagonistic action. The drug was tested alone and in combination with methyidopa in 23 subjects with uncomplicated primary severe hypertension (diastolic pressure > 120 mm Hg) in a short- and long-term therapeutic trial. Hourly pressure readings during the short-term period showed that the antihypertensive response to nifedipine (10 mg orally) is maximal within 40 minutes and lasts for 8-12 hours. When nifedipine is administered every 6 hours the tendency of blood pressure to rise after each dose is repressed by the next dose, so that pressure remains significantly reduced throughout the 24 hours; when methyidopa is combined (250 mg four times daily) blood pressure is further reduced toward normal, without significant fluctuations during the day. After 10 days of drug combination, the antihypertensive response was mediated through reduction of peripheral vascular resistance associated with increase in cardiac output. Renal function was unchanged or improved and sodium retention and plasma volume expansion were not promoted. In six patients with very severe hypertension (diastolic pressure > 140 mm Hg) complicated by cardiac failure, a dosing regimen every 4 hours of the two compounds promptly relieved dyspnea and lung congestion and, within 2-3 days, stabilized blood pressure to an average of 150/98 mm Hg. Persistence of the antihypertensive efficacy of this drug combination in a dosing regimen every 6 hours and its beneficial effects on heart size, ECG and fundi were documented in 22 subjects (four of whom belonged to the decompensated group) who completed a 12-month follow-up. A tendency in seven cases to ankle pitting or edema was the major side effect of nifedipine; the cause of this effect remains obscure.

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.

Negative influences of ascites on the cardiac function of cirrhotic patients

Right and left ventricular function was evaluated in 21 men with cirrhosis and tense ascites during staged removal of ascitic fluid. During paracentesis it was observed (1) that there was a significant increase in cardiac output, stroke volume, right and left ventricular stroke work and mean rate of systolic ejection; (2) that up to a certain stage of drainage (about 5,000 ml), there was a relationship between the amount of fluid removed and the intraabdominal and right atrial pressures and (3) that there was a direct relationship between improvement of cardiac function and normalization of right atrial pressure. It is believed that the increased intra-abdominal hydrostatic pressure acting upon the diaphragm affects the intrathoracic pressure to such an extent that the transmural filling pressure of the heart is reduced, and the mean pressure and respiratory pulsations of the right atrium increased, all of which impede venous return. Improved cardiac function during paracentesis appears to be due to an augmented filling of the heart and to a larger venous return.

Afterload reduction: a comparison of captopril and nifedipine in dilated cardiomyopathy.

Nifedipine and captopril are potent vasodilators and may be expected to help left ventricular failure by reducing afterload. Nifedipine (20 mg three times a day) and captopril (50 mg three times a day) were added to an optimal regimen of digitalis and diuretics in a double blind crossover trial in 18 cases of dilated cardiomyopathy. New York Heart Association functional class rating symptoms and exercise tolerance times improved on captopril but not on nifedipine. The reduction in pulmonary capillary wedge pressure and the increase of cardiac output on captopril indicated that the augmented functional capacity may have resulted in part from an improved performance of the left ventricle. Although there were comparable decreases in systemic vascular resistance and presumably in impedence to ejection by the left ventricle on both drugs, the dimensions of the ventricular cavity were found to be reduced by captopril and augmented by nifedipine, and only captopril reduced the afterload (wall stress). In addition, the force-length relation (between left ventricular end systolic stress and end systolic diameter) was shifted to the left of baseline by captopril and to the right by nifedipine, suggesting that muscle contractility was reduced by nifedipine and not by captopril. These results suggest that nifedipine and captopril have different effects on afterload and contractility and these may account for the different effects of these drugs on the performance of the heart and clinical responses.

Left and right heart haemodynamics during spontaneous angina pectoris. Comparison between angina with ST segment depression and angina with ST segment elevation.

The function of both right and left sides of the heart was studied during spontaneous attacks of angina pectoris at rest in 7 patients showing ST depression (type I) and 4 showing ST elevation (type II) during the attack. In none of the 44 type I attacks and 29 type II attacks which were recorded did circulatory changes; the latter were different in the two groups. Type I attacks showed: a) a brief fall in arterial pressure, accompanied by b) a rise of right atrial and pulmonary wedge pressures and c) a decrease of cardiac output, right and left stroke work, the mean rate of systolic ejection, and indirect left ventricular pre-ejection dP/dt. In the course of the attack a hypertensive phase followed, which was paralleled by an increase of heart rate, cardiac output, left and right stroke work, and mean systolic ejection rate, left dP/dt; right atrial pressure and wedge pressure remained raised. All of the circulatory functions started to revert towards the pre-attack levels coincident with the waning phase of the electrocardiographic alteration, the latter occurring either spontaneously or after nitroglycerin. Type II attacks for the entire duration of the electrocardiographic changes showed: a) a reduction of arterial pressure, cardiac output, right and left stroke work, mean systolic ejection rate, and left dP/dt, b) a rise of right atrial and wedge pressures, and c) quite small changes of heart rate. When the electrocardiogram started to revert to the pre-attack aspect, the cardiac function rapidly improved and, after a supernormal phase, returned to the basal levels in about 2 minutes. It is concluded: 1) that no circulatory factor interfering with the mechanical effort of the heart is responsible for eliciting spontaneous angina: 2) that in type I attacks right and left ventricular impairment occurs which recovers rapidly, possibly through a sympathetic compensation; 3) that in type II attachs dysfunction of both sides of the heart occurs and persists throughout the episode of electrocardiographic alteration; 4) that the dynamic impairment is probably more severe in type I than in type II angina.

Pulmonary hemodynamics and right ventricular function in hypertension.

SUMMARYPulmonary and systemic hemodynamics in 16 hypertensive subjects (group I) with left ventricular (LV) hypertrophy (ECG and echo criteria) and in 17 hypertensive subjects with ECG signs of LV strain (group II), were compared with those in 14 normal individuals. An augmented pulmonary arteriolar resistance (PAR) in group I and to a larger extent in group II accounted for the pulmonary pressure elevation in both groups. Increase in PAR was unrelated to pulmonary blood flow and volume, pleural pressure, arterial PO2, PCO2 and pH, and could not be explained entirely by the left ventricular end-diastolic pressure changes.In group I, left (L.MSEJR) and right (R.MSEJR) mean systolic ejection rate, stroke index (SI) and mean velocity of circumferential fiber shortening (VCF) were enhanced in spite of the heightened pressure load on both sides of the heart. In group II, a large reduction of SI, L.MSEJR, R.MSEJR and VCF, as well as the relationship between ventricular filling pressures and SI, documented a compromised performance of both ventricles.Findings indicate that: systemic hypertension is associated with elevation of pulmonary arterial pressure and of PAR which is not necessarily a consequence of impairment in LV function; LV hypertrophy is associated with enhanced performance of either ventricle; in coincidence with development of ECG signs of LV strain, the performance of both sides of the heart deteriorates.A functional interdependence of the two ventricles is suggested.

Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest

Syndrome X is characterized by an abnormal vasomotility of coronary microvessels. It is unknown whether the presence of an ischemic-like pattern in the electrocardiogram at rest (T-wave inversion) reflects a more severe vasomotion disturbance. Changes in coronary sinus flow (thermodilution) and epicardial vessel diameter (quantitative angiography) during adrenergic activation were measured with a standard cold pressor test in patients with syndrome X whose electrocardiogram at rest was normal (group 1: 17 patients) or showed stable, symmetrically inverted T waves (group 2: 22 patients). Cold pressor test increased mean blood pressure and rate-pressure product to a similar extent in both groups, increased coronary sinus flow in group 1 (88 +/- 29 to 119 +/- 36 ml/min; p less than 0.05) and not in group 2 (109 +/- 37 vs 104 +/- 36 ml/min; p = not significant), and decreased coronary resistance in group 1 (1.38 +/- 0.42 to 1.19 +/- 0.38 mm Hg/ml/min; p less than 0.05) and augmented it in group 2 (1.06 +/- 0.32 to 1.28 +/- 0.43 mm Hg/ml/min; p less than 0.02). During cold stimulus, the proximal and middle segments of epicardial arteries showed negligible changes in their lumen, whereas the distal segment dilated in group 1 (1.81 +/- 0.27 to 2.01 +/- 0.32 mm; p less than 0.05) and constricted in group 2 (1.82 +/- 0.12 to 1.62 +/- 0.20 mm; p less than 0.05). Differences in coronary hemodynamic and angiographic responses between the groups were statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)